Mark Reacher

Whole-genome sequencing to identify transmission of Mycobacterium abscessus between patients with cystic fibrosis: a retrospective cohort study

Summary Background Increasing numbers of individuals with cystic fibrosis are becoming infected with the multidrug-resistant non-tuberculous mycobacterium (NTM) Mycobacterium abscessus, which causes progressive lung damage and is extremely challenging to treat. How this organism is acquired is not currently known, but there is growing concern that person-to-person transmission could occur. We aimed to define the mechanisms of acquisition of M abscessus in individuals with cystic fibrosis. Method Whole genome sequencing and antimicrobial susceptibility testing were done on 168 consecutive isolates of M abscessus from 31 patients attending an adult cystic fibrosis centre in the UK between 2007 and 2011. In parallel, we undertook detailed environmental testing for NTM and defined potential opportunities for transmission between patients both in and out of hospital using epidemiological data and social network analysis. Findings Phylogenetic analysis revealed two clustered outbreaks of near-identical isolates of the M abscessus subspecies massiliense (from 11 patients), differing by less than ten base pairs. This variation represents less diversity than that seen within isolates from a single individual, strongly indicating between-patient transmission. All patients within these clusters had numerous opportunities for within-hospital transmission from other individuals, while comprehensive environmental sampling, initiated during the outbreak, failed to detect any potential point source of NTM infection. The clusters of M abscessus subspecies massiliense showed evidence of transmission of mutations acquired during infection of an individual to other patients. Thus, isolates with constitutive resistance to amikacin and clarithromycin were isolated from several individuals never previously exposed to long-term macrolides or aminoglycosides, further indicating cross-infection. Interpretation Whole genome sequencing has revealed frequent transmission of multidrug resistant NTM between patients with cystic fibrosis despite conventional cross-infection measures. Although the exact transmission route is yet to be established, our epidemiological analysis suggests that it could be indirect. Funding The Wellcome Trust, Papworth Hospital, NIHR Cambridge Biomedical Research Centre, UK Health Protection Agency, Medical Research Council, and the UKCRC Translational Infection Research Initiative.

The Association between Time Spent Outdoors and Myopia in Children and Adolescents: A Systematic Review and Meta-analysis.

OBJECTIVE To summarize relevant evidence investigating the association between time spent outdoors and myopia in children and adolescents (up to 20 years). DESIGN Systematic review and meta-analysis. PARTICIPANTS Results from 7 cross-sectional studies were pooled in a meta-analysis. A further 16 studies (8 cross-sectional not meeting criteria for meta-analysis; 7 prospective cohort studies; 1 randomized, controlled trial [RCT]) were reported in the systematic review. METHODS The literature search included 4 databases (Medline, Embase, Web of Science, and Cochrane Central Register of Controlled Trials [CENTRAL]), and reference lists of retrieved studies. Estimates of association were pooled using random effects meta-analysis. We summarized data examining the association between time spent outdoors and prevalent myopia, incident myopia, and myopic progression. MAIN OUTCOME MEASURES Pooled odds ratios (ORs) and 95% confidence intervals (CIs) for myopia for each additional hour spent outdoors per week from a meta-analysis. RESULTS The pooled OR for myopia indicated a 2% reduced odds of myopia per additional hour of time spent outdoors per week, after adjustment for covariates (OR, 0.981; 95% CI, 0.973-0.990; P<0.001; I(2), 44.3%). This is equivalent to an OR of 0.87 for an additional hour of time spent outdoors each day. Three prospective cohort studies provided estimates of risk of incident myopia according to time spent outdoors, adjusted for possible confounders, although estimates could not be pooled, and the quality of studies and length of follow-up times varied. Three studies (2 prospective cohort and 1 RCT) investigated time spent outdoors and myopic progression and found increasing time spent outdoors significantly reduced myopic progression. CONCLUSIONS The overall findings indicate that increasing time spent outdoors may be a simple strategy by which to reduce the risk of developing myopia and its progression in children and adolescents. Therefore, further RCTs are warranted to investigate the efficacy of increasing time outdoors as a possible intervention to prevent myopia and its progression.

Clinical Severity of Clostridium difficile PCR Ribotype 027: A Case-Case Study

Background Clostridium difficile is a leading infectious cause of health care associated diarrhoea. Several industrialised countries have reported increased C. difficile infections and outbreaks, which have been attributed to the emergent PCR ribotype 027 strain. Methods and Findings We conducted a case-case study to compare severity of C. difficile disease for patients with 027 versus non-027 ribotypes. We retrospectively collected clinical information about 123/136 patients with C. difficile infections admitted to hospitals in the East of England region in 2006 and from whom stool isolates were cultured and ribotyped as part of an earlier national survey. We defined severe C. difficile disease as having one or more of shock, paralytic ileus, pseudo membranous colitis or toxic megacolon. Patient median age was 83 years old (range 3 to 98, interquartile range 75 to 89), 86% were prescribed antibiotics in the eight weeks before illness onset, 41% had ribotype 027 and 30-day all cause mortality during hospital admission was 21%. Severe disease occurred in 24% (95%CI 13% to 37%) and 17% (95%CI 9% to 27%) of patients with PCR ribotype 027 and non-027 ribotypes respectively. In a multivariable model, ribotype 027 was not associated with severe disease after adjusting for sex, discharge from hospital prior to 60 days of current admission, gastroenteritis on admission, number of initiator antibiotics for C. difficile disease, and hospital where the patient was admitted. Conclusions Our study found no evidence to support previous assertions that ribotype 027 is more virulent than other PCR ribotypes. This finding raises questions about the contribution of this strain to the recent increase in C. difficile disease throughout North America and Europe.

Effect of 3 years of SAFE (surgery, antibiotics, facial cleanliness, and environmental change) strategy for trachoma control in southern Sudan : a cross-sectional study

BACKGROUND A trachoma control programme was started in southern Sudan in 2001. We did a 3-year evaluation to quantify uptake of SAFE (surgery, antibiotics, facial cleanliness, and environmental change) interventions, and to assess the prevalence of active trachoma and unclean faces. METHODS Cross-sectional surveys, including clinical assessment of trachoma (WHO simplified system) and structured questionnaires, were done in four intervention areas at baseline and follow-up. Process indicators were uptake of SAFE components; primary outcome indicators included trachomatous inflammation-follicular (TF) and unclean face in children aged 1-9 years. FINDINGS There was heterogeneous uptake of SAFE between intervention areas. Surgical coverage was low in all areas (range 0.5% of 428 individuals in Katigiri to 6% of 5002 in Kiech Kuon), antibiotic uptake ranged from 14% of 1257 individuals in Kiech Kuon to 75% of 954 in Katigiri, health education ranged from 49% of 190 households in Kiech Kuon to 90% of 182 in Padak, and latrine coverage from 3% of households in Tali to 16% in Katigiri. Substantial decreases in prevalence of TF and unclean faces were recorded in Katigiri and Tali, two of three sites where uptake of antibiotics and health education was high: TF decreased by 92% (95% CI 87-96) and 91% (86-95), respectively, and unclean face decreased by 87% (78-94) and 38% (22-52), respectively. Moderate effects were recorded in Padak, an area with high coverage, with a 28% (14-41) decrease in TF and a 16% (7-25) decrease in unclean face. No evidence of decline was seen in Kiech Kuon, where uptake of antibiotics and health education was low, with a 2% (-10 to 12) decrease in TF and a 10% (-3 to 23) decrease in unclean face. INTERPRETATION Our results show that substantial falls in active trachoma can occur where SAFE is implemented, and that good results could be achieved with the SAFE strategy in other trachoma-endemic areas.

Epidemiology of vitamin A deficiency and xerophthalmia in at-risk populations

Vitamin A deficiency (VAD) is an important public health problem worldwide that contributes significantly to the global burden of disease. Vitamin A deficiency disorders include xerophthalmia and increased risk of infectious diseases, both of which increase risk of mortality. Xerophthalmia is also a leading cause of preventable blindness. Areas with highly prevalent VAD often share common dietary and other environmental exposures, including poverty, infectious diseases, limited development and poor availability of vitamin A containing food. Globally, the prevalence of VAD has been declining, which may be due to widespread vitamin A supplementation in conjunction with measles immunisation in at-risk populations. Recent meta-analyses confirm that provision of vitamin A to children aged between 6 months and 5 years confers a significant mortality benefit. Further preventative measures for VAD comprise improving availability of vitamin A containing food, including foods biofortified with vitamin A. Ensuring vitamin A is available in any form in adequate quantities remains problematic, especially in areas affected by environmental catastrophes and conflict, and other areas where access to vitamin A containing foods and healthcare interventions is limited. Hence, it remains essential that maternal and child health workers remain vigilant for VAD in nutritionally vulnerable populations.

Prevalence and Causes of Blindness and Low Vision in Southern Sudan

Background Blindness and low vision are thought to be common in southern Sudan. However, the magnitude and geographical distribution are largely unknown. We aimed to estimate the prevalence of blindness and low vision, identify the main causes of blindness and low vision, and estimate targets for blindness prevention programs in Mankien payam (district), southern Sudan. Methods and Findings A cross-sectional survey of the population aged 5 y and above was conducted in May 2005 using a two-stage cluster random sampling with probability proportional to size. The Snellen E chart was used to test visual acuity, and participants also underwent basic eye examination. Vision status was defined using World Health Organization categories of visual impairment based on presenting visual acuity (VA). A total of 2,954 persons were enumerated and 2,499 (84.6%) examined. Prevalence of blindness (presenting VA of less than 3/60 in the better eye) was 4.1% (95% confidence interval [CI], 3.4–4.8); prevalence of low vision (presenting VA of at least 3/60 but less than 18/60 in the better eye) was 7.7% (95% CI, 6.7–8.7); whereas prevalence of monocular visual impairment (presenting VA of at least 18/60 in better eye and VA of less than 18/60 in other eye) was 4.4% (95% CI, 3.6–5.3). The main causes of blindness were considered to be cataract (41.2%) and trachoma (35.3%), whereas low vision was mainly caused by trachoma (58.1%) and cataract (29.3%). It is estimated that in Mankien payam 1,154 persons aged 5 y and above (lower and upper bounds = 782–1,799) are blind, and 2,291 persons (lower and upper bounds = 1,820–2,898) have low vision. Conclusions Blindness is a serious public health problem in Mankien, and there is urgent need to implement comprehensive blindness prevention programs. Further surveys are essential to confirm these tragic findings and estimate prevalence of blindness and low vision in the entire region of southern Sudan in order to facilitate planning of VISION 2020 objectives.

The epidemiology of trachoma in Eastern Equatoria and Upper Nile States, southern Sudan

OBJECTIVE Limited surveys and anecdotal data indicate that trachoma is endemic in the states of Eastern Equatoria and Upper Nile in southern Sudan. However, its magnitude and geographical distribution are largely unknown. We conducted surveys to ascertain the prevalence and geographical distribution of trachoma, and to identify targets for control interventions. METHODS Population-based cross-sectional surveys were conducted in nine sites in southern Sudan between September 2001 and June 2004. Two-stage random cluster sampling with probability proportional to size was used to select the sample. Trachoma grading was done using the WHO simplified grading system. FINDINGS A total of 17 016 persons were examined, a response rate of 86.1% of the enumerated population. Prevalence of signs of active trachoma in children aged 1-9 years was: TF=53.7% (95% confidence interval (CI)=52.1-55.3); TI=42.7% (95% CI=41.2-44.2); TF and/or TI=64.1% (95% CI=62.5-65.5). Prevalence of trichiasis (TT) in children aged less than 15 years was 1.2% (95% CI=0.9-1.4), while TT prevalence in persons aged 15 years and above was 9.2% (95% CI=8.6-9.9). Women were more likely to have trichiasis compared to men (odds ratio (OR)=1.57; 95% CI=1.34-1.84). Tentative extrapolation to the states of Eastern Equatoria and Upper Nile estimates that there is a backlog of 178,250 (lower and upper bounds=156,027-205,995) persons requiring surgery and the entire population, estimated to be over 3.9 million, is in need of the SAFE strategy to control blinding trachoma. CONCLUSION Trachoma is a public health problem in all nine of the study sites surveyed. The unusually high prevalence of active trachoma and TT in children points to the severity of the problem. There is urgent need to implement trachoma control interventions in trachoma endemic regions of southern Sudan.

Associations between Active Trachoma and Community Intervention with Antibiotics, Facial Cleanliness, and Environmental Improvement (A,F,E)

Background Surgery, Antibiotics, Facial cleanliness and Environmental improvement (SAFE) are advocated by the World Health Organization (WHO) for trachoma control. However, few studies have evaluated the complete SAFE strategy, and of these, none have investigated the associations of Antibiotics, Facial cleanliness, and Environmental improvement (A,F,E) interventions and active trachoma. We aimed to investigate associations between active trachoma and A,F,E interventions in communities in Southern Sudan. Methods and Findings Surveys were undertaken in four districts after 3 years of implementation of the SAFE strategy. Children aged 1–9 years were examined for trachoma and uptake of SAFE assessed through interviews and observations. Using ordinal logistic regression, associations between signs of active trachoma and A,F,E interventions were explored. Trachomatous inflammation-intense (TI) was considered more severe than trachomatous inflammation-follicular (TF). A total of 1,712 children from 25 clusters (villages) were included in the analysis. Overall uptake of A,F,E interventions was: 53.0% of the eligible children had received at least one treatment with azithromycin; 62.4% children had a clean face on examination; 72.5% households reported washing faces of children two or more times a day; 73.1% households had received health education; 44.4% of households had water accessible within 30 minutes; and 6.3% households had pit latrines. Adjusting for age, sex, and district baseline prevalence of active trachoma, factors independently associated with reduced odds of a more severe active trachoma sign were: receiving three treatments with azithromycin (odds ratio [OR] = 0.1; 95% confidence interval [CI] 0.0–0.4); clean face (OR = 0.3; 95% CI 0.2–0.4); washing faces of children three or more times daily (OR = 0.4; 95% CI 0.3–0.7); and presence and use of a pit latrine in the household (OR = 0.4; 95% CI 0.2–0.9). Conclusion Analysis of associations between the A,F,E components of the SAFE strategy and active trachoma showed independent protective effects against active trachoma of mass systemic azithromycin treatment, facial cleanliness, face washing, and use of pit latrines in the household. This strongly argues for continued use of all the components of the SAFE strategy together.

Blinding trachoma in postconflict southern Sudan

Background Trachoma is a leading cause of preventable blindness. Reports from eye surgery camps and anecdotal data indicated that blinding trachoma is a serious cause of visual impairment in Mankien payam (district) of southern Sudan. We conducted this study to estimate the prevalence of trachoma, estimate targets for interventions, and establish a baseline for monitoring and evaluation. Methods and Findings A population-based cross-sectional survey was conducted in May 2005. A two-stage cluster random sampling with probability proportional to size was used to select the sample population. Participants were examined for trachoma by experienced graders using the World Health Organization simplified grading scheme. A total of 3,567 persons were examined (89.7% of those enumerated) of whom 2,017 were children aged less than 15 y and 1,550 were aged 15 y and above. Prevalence of signs of active trachoma in children aged 1–9 y was: trachomatous inflammation-follicular (TF) = 57.5% (95% confidence interval [CI], 54.5%–60.4%); trachomatous inflammation-intense (TI) = 39.8% (95% CI, 36.3%–43.5%); and TF and/or TI (active trachoma) = 63.3% (95% CI, 60.1%–66.4%). Prevalence of trachomatous trichiasis was 9.6% (95% CI, 8.4%–10.9%) in all ages, 2.3% (95% CI, 1.6%–3.2%) in children aged under 15 y, and 19.2% (95% CI, 17.0%–21.7%) in adults. Men were equally affected by trichiasis as women: odds ratio = 1.09 (95% CI, 0.81%–1.47%). It is estimated that there are up to 5,344 persons requiring trichiasis surgery in Mankien payam. Conclusions Trachoma is a serious public health problem in Mankien, and the high prevalence of trichiasis in children underscores the severity of blinding trachoma. There is an urgent need to implement the surgery, antibiotics, facial cleanliness, and environmental change (SAFE) strategy for trachoma control in Mankien payam, and the end of the 21-y civil war affords an opportunity to do this.

Linking healthcare associated norovirus outbreaks: a molecular epidemiologic method for investigating transmission

BackgroundNoroviruses are highly infectious pathogens that cause gastroenteritis in the community and in semi-closed institutions such as hospitals. During outbreaks, multiple units within a hospital are often affected, and a major question for control programs is: are the affected units part of the same outbreak or are they unrelated transmission events? In practice, investigators often assume a transmission link based on epidemiological observations, rather than a systematic approach to tracing transmission.Here, we present a combined molecular and statistical method for assessing:1) whether observed clusters provide evidence of local transmission and2) the probability that anecdotally|linked outbreaks truly shared a transmission event.Methods76 healthcare associated outbreaks were observed in an active and prospective surveillance scheme of 15 hospitals in the county of Avon, England from April 2002 to March 2003. Viral RNA from 64 out of 76 specimens from distinct outbreaks was amplified by reverse transcription-PCR and was sequenced in the polymerase (ORF 1) and capsid (ORF 2) regions. The genetic diversity, at the nucleotide level, was analysed in relation to the epidemiological patterns.ResultsTwo out of four genetic and epidemiological clusters of outbreaks were unlikely to have occurred by chance alone, thus suggesting local transmission. There was anecdotal epidemiological evidence of a transmission link among 5 outbreaks pairs. By combining this epidemiological observation with viral sequence data, the evidence of a link remained convincing in 3 of these pairs. These results are sensitive to prior beliefs of the strength of epidemiological evidence especially when the outbreak strains are common in the background population.ConclusionThe evidence suggests that transmission between hospitals units does occur. Using the proposed criteria, certain hypothesized transmission links between outbreaks were supported while others were refuted. The combined molecular/epidemiologic approach presented here could be applied to other viral populations and potentially to other pathogens for a more thorough view of transmission.